See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/244230562 Solid phase synthesis of α-acylamino-α,αdisubstituted ketones ARTICLE in TETRAHEDRON LETTERS · OCTOBER 2002 Impact Factor: 2.38 · DOI: 10.1016/S0040-4039(02)01803-8 CITATIONS READS 11 29 6 AUTHORS, INCLUDING: Colin M Tice Ernesto Nicolás 53 PUBLICATIONS 815 CITATIONS University of Barcelona SEE PROFILE 57 PUBLICATIONS 775 CITATIONS SEE PROFILE Javier Garcia Fernando Albericio Hospital Universitario de Salamanca University of KwaZulu-Natal 28 PUBLICATIONS 866 CITATIONS 778 PUBLICATIONS 12,626 CITATIONS SEE PROFILE SEE PROFILE Available from: Ernesto Nicolás Retrieved on: 10 January 2016 TETRAHEDRON LETTERS Tetrahedron Letters 43 (2002) 7491–7494 Pergamon Solid phase synthesis of a-acylamino-a,a-disubstituted ketones Colin M Tice,a,* Enrique L Michelotti,b,† Ernesto G Mata,b,c Ernesto Nicola`s,d Javier Garciab,d and Fernando Albericiod,* a RHeoGene Inc., PO Box 949, 727 Norristown Road, Spring House, PA 19477 -0949, USA Rohm and Haas Company, PO Box 904, 727 Norristown Road, Spring House, PA 19477 -0904, USA c Instituto de Quı´mica Orga´nica de Sı´ntesis, CONICET-Universidad Nacional de Rosario, Rosario, Argentina d Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain b Received 12 August 2002; revised 23 August 2002; accepted 26 August 2002 Abstract—a-Acylamino-a,a-disubstituted ketones are of interest as ecdysone agonists Solid phase synthesis of prototypical a-acylamino-a,a-disubstituted ketones on two different solid supports is described In both cases the ketone was formed by reaction of a Grignard reagent with an N-acyl-a,a-disubstituted amino acid immobilized through its carboxylate as a Weinreb amide derivative © 2002 Elsevier Science Ltd All rights reserved As part of a program to discover ecdysone agonists for use in systems to control gene expression via natural and engineered ecdysone receptors, we became interested in a-acylaminoketones of general structure With appropriate substituents at the R1, R1a, R2 and R3 positions, these compounds are potentially bioisosteric with known diacyl hydrazine ecdysone agonists e.g (Fig 1).1,2 To investigate this hypothesis we sought a solid phase synthesis of which would be sufficiently general to allow production of a library of compounds for biological screening Figure a-Acylamino-a,a-disubstituted ketones and diacylhydrazine Abbreviations: Aib, a-aminoisobutyric acid; DIC, N,N%-diisopropylcarbodiimide; EDC, 1-ethyl-3-(3%-dimethylaminopropyl)carbodiimide; Fmoc, 9-fluorenylmethoxycarbonyl; HOAt, 1-hydroxy-7-azabenzotriazole; HATU, N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; i-Pr2Net, N,N-diisopropylethylamine; NMP, N-methylpyrrolidin-2-one; PAS-FTIR, photoacoustic Fourier transform infrared spectroscopy; TFA, trifluoroacetic acid; TFFH, tetramethylfluoroformamidinium hexafluorophosphate * Corresponding authors † Current address: Locus Discovery Inc., Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, USA A number of solid phase syntheses of ketones,3–22 including a-acylaminoketones,10–22 have been reported in the literature The syntheses of a-acylaminoketones have utilized a variety of strategies to link the synthetic intermediates to the polymeric support including linking through the nitrogen,10–12 through a functional group remote from the ketone,13–17 through the ketone itself as a hydrazone derivative18–20 or employing a carboxylic acid derivative as the incipient ketone.21,22 We were particularly attracted to the last approach since it would allow complete construction of the desired compounds on solid phase (Scheme 1) Thus, resin bound Weinreb amides could plausibly be assembled from N-protected a,a-disubstituted amino acids and carboxylic acids Treatment of with Grignard reagents should liberate the desired aacylaminoketones Large numbers of carboxylic acids and certain N-protected a,a-disubstituted amino acids and Grignard reagents are commercially available rendering production of a large library a practical undertaking However, a,a-disubstituted amino acids are known to be problematic in peptide synthesis because of their steric bulk23 and we anticipated that we might encounter similar difficulties using them Furthermore, during the course of this work, O’Donnell and Scott reported that t-BuMgBr failed to give any of the desired ketone when reacted with a resin bound intermediate not dissimilar to 3, suggesting that the addition of a Grignard reagent to a resin bound Weinreb amide is susceptible to steric hindrance.22 Nonetheless, we embarked upon an effort to reduce the 0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd All rights reserved PII: S 0 - ( ) - 7492 C M Tice et al / Tetrahedron Letters 43 (2002) 7491–7494 Scheme Retrosynthesis of a-acylamino-a,a-disubstituted ketones approach outlined retrosynthetically in Scheme to practice, initially using the benzyloxyamino resin reported by Salvino8 and subsequently employing the commercially available Weinreb amide resin 13 developed by Martinez.24 Benzyloxyamino resin (Scheme 2) was prepared from Wang resin following the literature procedure8 and the intermediates were characterized by PAS-FTIR Product resin itself was characterized both by PASFTIR and by cleavage of a portion with TFA/CH2Cl2 (1:1) to afford C6H5CH2ONH2 Fmoc-Aib-OH (6a) was selected as a prototypical a,a-disubstituted amino acid for coupling to and the extent of conversion of to 9a was estimated based on PAS-FTIR.25 A number of standard peptide coupling conditions were explored and failed to give satisfactory conversion to the amide 9a (Table 1, entries 1–6) Use of the amino acid fluoride prepared in situ using TFFH (entry 7) or isolated from reaction of Fmoc-Aib-OH and DAST (entry 8)26 afforded slightly improved conversion Proceeding through the synthetic sequence with incompletely loaded samples of 9a proved problematical Benzyloxyamino groups that had not reacted with 6a were available for coupling with benzoic acid (7a) affording 10 (Scheme 3) Grignard reagents effectively converted 10 to phenyl ketones 11 Finally, significantly improved loading was effected using the symmetrical anhydride of 6a, prepared in situ by treatment of 6a with 0.5 equiv of DIC in a mixture of CH2Cl2 and DMF (entry 9).27 Submitting the resin to a second cycle of coupling increased the level of conversion of to 9a to 91% (entry 10) The Fmoc protecting group was removed from 9a under standard conditions and benzoic acid was smoothly coupled to the free amino group using DIC/HOAt to afford 3a Resin bound intermediates 9a and 3a exhibited satisfactory PAS-FTIR spectra Treatment of 3a with excess EtMgBr afforded 1a in 60% yield based on the initial functionalization of the resin The chemistry was successfully extended to aromatic Grignard reagents Reaction of 3a with excess of PhMgBr afforded 1b in 31% yield The major impurity in the crude product was biphenyl derived from the Grignard solution used Examination of the spent resin from this reaction by PAS-FTIR revealed the presence of peaks corresponding to unreacted 3a, possibly accounting for the low yield Reaction of 3a with 4-methoxyphenylmagnesium bromide failed to give 1c; H NMR and LC MS indicated that the major component in the crude product was 4,4%-dimethoxy-1,1%biphenyl, present in the Grignard solution used Furthermore, application of the optimum coupling conditions developed for Fmoc-Aib-OH to Fmoc protected 1-aminocyclohexane-1-carboxylic acid (6b) gave only 37% conversion to amide 9b by PAS-FTIR The difficulties in effecting complete coupling of 6a to and in achieving efficient reaction of 3a with Grignard reagents were apparently due at least in part to steric hindrance around the benzyloxyamino functionality This prompted us to explore the use of methoxyamino resin 13, available by deprotection of commercially available 12 (Scheme 4) The methoxyamino group in 13 is presumably more accessible than the benzyloxyamino group in Acylation of 13 with Fmoc-AibOH (6a) was carried out using the symmetric anhydride of 6a under conditions described above (Table 1, entry 10) to afford 14 with 66% conversion Removal of the Fmoc protecting group with piperidine in DMF gave 15 and coupling benzoic acid (7a) to the free amino group afforded 16 Treatment of 16 with excess of EtMgBr (4a) provided 1a in 51% yield based on the Scheme (a) FmocNHCR1R1aCO2H (6, 10 equiv.), DIC (5 equiv.), CH2Cl2/DMF (7:3), days, rt; (b) piperidine/DMF (1:4), 20 min, rt; (c) PhCO2H (7a, 10 equiv.), DIC (10 equiv.), HOAt (10 equiv.), h, rt; (d) R2MgBr (4, 10 equiv.), THF(anh), 18 h, rt Scheme (a) PhCO2H (10 equiv.), DIC (10 equiv.), HOAt (10 equiv.), h, rt; (b) R2MgBr (4, 10 equiv.), THF(anh), 18 h, rt C M Tice et al / Tetrahedron Letters 43 (2002) 7491–7494 7493 Table Optimization of loading Fmoc-Aib-OH (6a) onto resin 8a Entry Reagents (equivs) Solvent Time (days) Conversionb 10 6a (4), DIC (4), HOAt (4) 6a (4), DIC (4), HOAt (4) 6a (4), HATU (4), i-Pr2NEt (8) 6a (5), EDC (5) 6a (5), EDC (5), HOAt (4.5) 6a (5), DIC (5), HOAt (5), i-Pr2NEt (5) 6a (5), TFFH (5), i-Pr2NEt (10) Fmoc-Aib-F (5)c (Fmoc-Aib)2O (5)d (Fmoc-Aib)2O (5)d DMF DMF DMF DMF DMF NMP DMF DCM DCM/DMF (7:3) DCM/DMF (7:3) 2×3 3 3 2×3 28 32 20 15 30 20 40 42 83 91 a All reactions were run at room temperature The conversion was measured by photoacoustic infrared spectroscopy See Ref 25 c Fmoc-Aib-F, the acid fluoride of 6a, was prepared from 6a and DAST See Ref 26 d (Fmoc-Aib)2O, the symmetrical anhydride of 6a, was prepared immediately prior to use by treatment of 6a with 0.5 equiv of DIC See Ref 27 b Scheme (a) piperidine/DMF (1:4), 20 min, rt; (b) Fmoc-Aib-OH (6a, 10 equiv.), DIC (5 equiv.), CH2Cl2/DMF (7:3), days, rt; (c) piperidine/DMF (1:4), 20 min, rt; (d) PhCO2H (7a, 10 equiv.), DIC (10 equiv.), HOAt (10 equiv.), h, rt; (e) R2MgBr (4, 10 equiv.), THF(anh), 18 h, rt initial functionalization of the resin while excess PhMgBr (4b) afforded 1b in 36% yield.28 Again, the major impurity in 1b was biphenyl and examination of the spent resin revealed the presence of peaks corresponding to unreacted 16 Based on these results, resin 13 did not offer any improvement over In conclusion, we demonstrated solid phase synthesis of prototypical a-acylamino-a,a-disubstitutedketones 1a and 1b However, the purity of the crude products, resulting from inefficient conversion in certain steps and the presence of typical side-products formed during the Grignard reactions in the cleavage solution, does not make this route the most suitable for library production References Wing, K D.; Slawecki, R A.; Carlson, G R Science 1988, 241, 470–472 Carlson, G R.; Cress, D E.; Dhadialla, T S.; Hormann, R E.; Le, D P US Patent 6,258,603, 2001; Chem Abstr 2001, 135, 72148 Cody, D R.; De Witt, S H H.; Hodges, J C.; Kiely, J S.; Moos, W H.; Pavia, M R.; Roth, B D.; Schroeder, M C.; Stankovic, C J US 5,324,483, 1994 (Chem Abstr 1995, 122:106536 ) Dinh, T Q.; Armstrong, R W Tetrahedron Lett 1996, 37, 1161–1164 Porco, J A., Jr.; Deegan, T.; Devenport, W.; Gooding, O W.; Heisler, K.; Labadie, J W.; Newcomb, B.; Nguyen, C.; van Eikeren, P.; Wong, J.; Wright, P Mol Diversity 1997, 2, 197–206 Wallace, O B Tetrahedron Lett 1997, 38, 4939–4942 Lee, C E.; Kick, E K.; Ellman, J A J Am Chem Soc 1998, 120, 9735–9747 Salvino, J M.; Mervic, M.; Mason, H J.; Kiesow, T.; Teager, D.; Airey, J.; Labaudiniere, R J Org Chem 1999, 64, 1823–1830 May, P J.; Bradley, M.; Harrowven, D C.; Pallin, D Tetrahedron Lett 2000, 41, 1627–1631 10 Kim, S W.; Bauer, S M.; Armstrong, R W Tetrahedron Lett 1998, 39, 6993–6996 11 Yamashita, D S.; Dong, X.; Oh, H.-J.; Brook, C S.; Tomaszek, T A.; Szewczuk, L.; Tew, D G.; Veber, D F J Comb Chem 1999, 1, 207–215 12 Fenwick, A D.; Garnier, B.; Gribble, A D.; Ife, R J.; Rawlings, A D.; Witherington, J Bioorg Med Chem Lett 2001, 11, 195–198 13 Zhang, C.; Moran, E J.; Woiwode, T F.; Short, K M.; Mjalli, A M M Tetrahedron Lett 1996, 37, 751–754 14 Miller, P C.; Owen, T J.; Molyneaux, J M.; Curtis, J M.; Jones, C R J Comb Chem 1999, 1, 223–224 15 Abato, P.; Conroy, J L.; Seto, C T J Med Chem 1999, 42, 4001–4009 16 Nishida, A.; Fuwa, M.; Naruto, S.; Sugano, Y.; Saito, H.; Nakagawa, M Tetrahedron Lett 2000, 41, 4791– 4794 7494 C M Tice et al / Tetrahedron Letters 43 (2002) 7491–7494 17 Clapham, B.; Spanka, C.; Janda, K D Org Lett 2001, 3, 2173–2176 18 Poupart, M A.; Fazal, G.; Goulet, S.; Mar, L T J Org Chem 1999, 64, 1356–1361 19 Lee, A.; Huang, L.; Ellman, J A J Am Chem Soc 1999, 121, 9907–9914 20 Subramanayam, C.; Chang, S P Tetrahedron Lett 2000, 41, 7145–7149 21 Vlattas, I.; Dellureficio, J.; Dunn, R.; Sytwu, I I.; Stanton, J Tetrahedron Lett 1997, 38, 7321–7324 22 O’Donnell, M J.; Drew, M D.; Pottorf, R S.; Scott, W L J Comb Chem 2000, 2, 172–181 23 Humphrey, J M.; Chamberlain, A R Chem Rev 1997, 2243–2266 24 Fehrentz, J A.; Paris, M.; Heitz, A.; Velek, J.; Liu, C F.; Winternitz, F.; Martinez, J Tetrahedron Lett 1995, 43, 7871–7874 25 To provide a reference standard, Fmoc-Gly-OH (6c) was coupled to resin to afford 9c (Scheme 2) Complete conversion was demonstrated by magic angle spinning 1H NMR The carbamate (1722 cm−1) and amide carbonyl (1665 cm−1) stretches in the PAS-FTIR of 9c were integrated and normalized with respect to the aromatic C C stretch (1611 cm−1) Comparison of the normalized integrals of the carbamate and amide carbonyl stretches in samples of 9a allowed % conversion to be estimated These values were confirmed in certain cases by measuring the UV absorbance of the piperidine–dibenzofluvene adduct released when the Fmoc group was removed from 9a 26 Kaduk, C.; Holger, W.; Beyermann, M.; Forner, K.; Carpino, L A.; Biernet, M Lett Peptide Sci 1995, 2, 285–288 27 Mixtures of CH2Cl2 and DMF are better than DMF alone for the solid phase acylation of hindered amines See: Jensen, K J.; Alsina, J.; Songster, M F.; Va´ gner, J.; Albericio, F.; Barany, G J Am Chem Soc 1998, 120, 5441–5452 28 The following experimental procedure is representative Preparation of 16 Fmoc-Aib-OH (6a, 0.615 g, 1.89 mmol, 10 equiv.) and DIC (0.146 mL, 0.945 mmol, equiv.) were dissolved in mL of CH2Cl2/DMF (7:3) The mixture was stirred at room temperature for 10 min, the resultant precipitate (N,N%-diisopropylurea) was removed by filtration, and the filtrate was added to methoxyamino resin 13 (0.3 g, 0.189 mmol, 0.63 mmol/g) The mixture was shaken at room temperature for days and drained The resin was washed with DMF (10×5 mL), and CH2Cl2 (10×5 mL) to afford 14 PAS-FTIR Fmoc carbamate C O stretch: 1726 cm−1, amide C O stretch 1632 cm−1, resin amide C O stretch 1678 cm−1 The conversion was 66% determined by PAS-FTIR Resin 14 (0.3 g, 0.189 mmol, 0.63 mmol/g) was suspended in 20% piperidine in DMF (7 mL), and the reaction mixture was stirred for 20 The solution was drained, and the resin was washed thoroughly with DMF (5×5 mL), and CH2Cl2 (5×5 mL) to leave 15 To the obtained resin 15 was added benzoic acid (0.231 g, 1.89 mmol, 10 equiv.), HOAt (0.257 g, 1.89 mmol, 10 equiv.), and DIC (0.293 mL, 1.89 mmol, 10 equiv.) in mL of DMF The reaction was shaken for h and drained The resin was washed with DMF (5×5 mL) and CH2Cl2 (5×5 mL) to afford 16 PAS-FTIR resin amide C O stretch 1678 cm−1, amide bound to the solid support C O stretch: 1631 cm−1, benzamide C O stretch 1653 cm−1 Preparation of 1b To a suspension of 16 (0.1 g, 0.063 mmol, 0.63 mmol/g), in anhydrous THF (2 mL) under an atmosphere of argon was added a M solution of phenylmagnesium bromide in THF (4b, 0.63 mL, 0.63 mmol, 10 equiv.) The reaction mixture was shaken for 18 h and quenched by addition of M HCl:THF (1:1) The pH of the resulting solution was The mixture was stirred for 30 The solution was drained into a vial, and the resin was washed with THF (3×2 mL) The combined filtrates were evaporated to dryness, and the residue was dissolved in THF The solution was applied to a silica gel solid phase extraction cartridge which was eluted with CH2Cl2 (2×2 mL) The eluate was concentrated to leave a crude product (21 mg) containing 38% of 1b and 46% of biphenyl The crude product was subjected to flash chromatography using hexane:ethyl acetate (1:1), and the appropriate fractions were pooled and evaporated to give 1b (6 mg, 36%) as a white solid 1H NMR (300 MHz, CDCl3): l 1.63 (s, 6H), 6.84 (bs, 1H), 7.30–7.57 (aromatic H’s, 8H), 7.88 (dd, J=8, 1.6 Hz, 2H) MS (ESI, positive ion): m/z 268.3 (M+1)+ In addition biphenyl (10 mg) was isolated 1H NMR (300 MHz, CDCl3): l 7.25–7.45 (aromatic H’s, 6H), 7.64 (dd, J=7.6, 1.2 Hz, 4H)